We will conduct a comprehensive molecular epidemiologic investigation of the role that genetic variation in the NF-kappaB pathway plays in ovarian cancer etiology. Substantial evidence suggests that inflammation, apoptosis, and immune response processes are linked to ovarian carcinogenesis. NF-kappaB is a family of transcription factors central to these processes which regulates the expression of numerous genes. We hypothesize that genetic variation in NF-kappaB subunits or NF-kappaB inhibitors and activators may modify the activity of NF-kappaB and lead to inter-individual differences in inflammation, apoptosis, and immune response. We will use a three-phase study design to examine whether this genetic variation (specifically, over 3,000 informative polymorphisms in 260 NF-kappaB-related genes) is associated with risk of ovarian cancer. The first two phases of this work will consist of a split-sample group sequential analysis of participants recruited in ongoing ovarian cancer studies at the Mayo Clinic in Rochester, MN and at Duke University in Durham, NC including 1,700 cases and 1,800 frequency-matched controls. The third phase of our study consists of external validation of approximately 50 polymorphisms using data from ongoing studies at the Queensland Institute of Medical Research, Australia, and the University of Cambridge, UK. This comprehensive pathway-based, multiple-phase, linkage disequilibrium-focused approach incorporates design elements at the forefront of epidemiologic methodology. In total, this study will provide excellent statistical power to detect moderately-increased odds ratios. Our goal is to identify the subset of genes which are most relevant to ovarian cancer from among 260 candidate genes encoding NF-kappaB subunits and regulatory molecules. The shortlist of genes and genetic variants showing replicated associations throughout each phase of the study will then be transitioned into downstream functional analysis by our transdisciplinary team for the identification of future preventive and therapeutic strategies.